We have identified a chromosome 4p haplotype which segregates with L-dopa responsive, Lewy body parkinsonism. The haplotype also co-segregates with a phenotype of essential tremor prevalent in the family. Statistical evidence suggests this region is likely to contain the mutant gene responsible for these alternate phenotypes. We have identified two other families (independent datasets) to support our claim. An Italian kindred which shares chromosome 4p markers that segregate with early-onset Parkinson's disease and Family J (Wisconsin) with early onset Parkinson's diseases that strikingly resembles (clinically, Pathologically and geographically) disease in the Iowa kindred. This latter remains to be genetically and genealogically linked but is likely to be an additional branch. Using these resources, and additional families identified by the Clinical and Linkage Cores, our application is to use positional cloning strategies to identify the mutant gene. This will be achieved by the following techniques: (1) further genetic analysis of families putatively linked to chromosome 4p to refine a minimal haplotype (genetic analyses will include heterogeneity testing, multipoint/haplotype analysis of cross-over data and fine mapping using linkage disequilibrium): (2) rapid cDNA candidates gene sequencing from the linked interval; (3) construction and definition of a physical map (minimal framework contig in YACs, redundant tiling path in PACs, STS, STRP and EST localization); (4) gene identification (EST extention using full length cDNA libraries, exon trapping/cDNA selection, intron/exon genomic organisation, expression analysis) followed by gene sequencing in the search for mutation(s) segregating with early onset parkinsonism. Our subsidiary goals are to determine the importance of this locus in other familiar and idiopathic parkinsonian syndromes, in part through collaboration with the Epidemiology and Genetics of Parkinson's Disease Project (P.I. Walter Rocca, Co-PI Dernetriuus Maraganore).